Endoscopic mucosal resection : Early experience in British Columbia

Department of Medicine, Division of Gastroenterology, St Paul’s Hospital, University of British Columbia, Vancouver, British Columbia Correspondence: Dr Robert Enns, Pacific Gastroenterology Associates, Suite 770-1190 Hornby Street, Vancouver, British Columbia V6Z 2K5. Telephone 604-688-6332 ext 222, fax 604-689-2004, e-mail renns@interchange.ubc.ca Received for publication July 8, 2009. Accepted August 27, 2009 Barrett’s esophagus is believed to be a complication of longstanding gastroesophageal reflux disease (GERD), resulting in the replacement of the normal squamous lining of the distal esophagus by columnar epithelium, also known as specialized intestinal metaplasia (SIM). Endoscopic surveillance is recommended for patients with Barrett’s esophagus because of its malignant potential. However, management of Barrett’s esophagus in the setting of high-grade dysplasia (HGD) or mucosal-based adenocarcinoma is controversial. Traditionally, esophagectomy has been recommended for patients with HGD found during surveillance. However, the peri/postoperative mortality rate depends on institution experience, with those performing more procedures attaining lower mortality rates than less experienced centres (1,2). Moreover, original artiClE

long-term functional problems such as dysphagia may persist (3,4).The high mortality and morbidity rates associated with esophagectomy have encouraged the development of endoscopic techniques to manage dysplastic epithelium.
Photodynamic therapy (PDT) is based on the ability of chemical agents, known as photosensitizers, to produce cytotoxicity in the presence of oxygen after stimulation by light of an appropriate wavelength.Although advantages include ease of use and cost when compared with surgery (5-7), longterm data comparing esophagectomy and PDT are comparable.An observational study (8) involving 199 patients with fiveyear follow-up found similar survival rates between PDT and esophagectomy (overall mortality 9% versus 8.5%, respectively).Moreover, PDT for HGD reduces, but does not eliminate, the risk of progression to cancer because recurrences may be high as 13% despite treatment (9).Disadvantages include photosensitivity, which may last for six weeks, and symptomatic esophageal strictures.
Radiofrequency ablation (RFA) is a newer method for treating HGD.RFA uses radiofrequency energy delivered by a balloon fitted with a series of closely spaced electrodes (10).Thermal destruction of cells at a controlled depth results in low rates of stricture formation and buried metaplasia, which are the main advantages of ablative therapy.Initial results for this system are promising (11)(12)(13); however, ablative techniques do not permit identification of foci of invasive carcinoma not detected in biopsy samples which, in turn, may not have been treated adequately.
Endoscopic mucosal resection (EMR) of the esophagus has been proposed as a suitable method for managing patients with either HGD or intramucosal cancers (14,15) (Figure 1).We describe our experience using EMR for the treatment of Barrett's esophagus with dysplasia or intramucosal adenocarcinoma, assessing long-term effectiveness and complications.

METHODS
All patients referred to St Paul's Hospital (Vancouver, British Columbia) from 2004 to 2007 with Barrett's esophagus exhibiting either dysplasia (both HGD and low-grade dysplasia [LGD]) or early adenocarcinoma were considered for EMR and included in the analysis.St Paul's Hospital is a tertiary care facility and is a provincial referral hospital for therapeutic endoscopy (including EMR).All procedures were performed by one experienced endoscopist (RE).Patients were identified in the electronic medical system and their charts were systematically reviewed.Demographic data including age, sex, duration of reflux, use of proton pump inhibitor therapy and history of other endoscopic interventions (eg, dilation for stricture) were collected.Patients were excluded if they had less than one year of follow-up or had undergone other ablative procedures such as PDT or RFA.

EMR
Patients were sedated with intravenous midazolam and meperidine as per St Paul's Hospital conscious sedation guidelines.Patients were staged with an aggressive biopsy protocol using 'jumbo' forceps to biopsy every centimetre of four quadrants of Barrett's esophagus.Individuals with adenocarcinoma underwent endoscopic ultrasound imaging and computed tomography scanning for staging.Patients with dysplasia or early adenocarcinoma were offered EMR using a multiband mucosectomy device (Duette, Cook Medical, USA).Using the endoscopic banding resection technique, no submucosal injection was used.The lesion was directly aspirated into the cap and snared with a hexagonal snare with standard electrocautery settings.Resected specimens of all 22 patients were recovered in their entirety.There was no limit to the number of resections per session; however, circumferential resections (Figure 2) were avoided.EMR was repeated at six-to eightweek intervals until there was no endoscopic evidence of HGD on biopsy.Patients were then surveyed with the biopsy protocol every three to six months.If there was no evidence of dysplasia at six months, patients were followed annually.

Analysis
The primary outcome measure of interest was the effectiveness of EMR in treating dysplastic changes associated with Barrett's esophagus.Effectiveness was defined as no LGD on endoscopic biopsies after two years.The secondary outcome was complications.Because this was a retrospective, observational study, results were presented as descriptive statistics.Means ± SDs were used to report continuous variables following a normal distribution.Medians with ranges were used to report nonnormal continuous variables.
Written approval for the study was obtained from the local ethics committee, conducted in accordance with the Declaration of Helsinki.

RESULTS
Twenty-two patients with Barrett's esophagus and HGD or adenocarcinoma who underwent EMR were identified.The mean age of the patients was 67±10.6 years, all of whom were men.All patients were on a proton pump inhibitor and reported a median GERD history of 17 years (range four to 40 years).The mean length of Barrett's esophagus was 5.5±3.5 cm (Table 1).

Figure 1) Endoscopic mucosal resection. Endoscopic view through a bander
One patient had no dysplasia (nodule), three had LGD, 15 had HGD and three had adenocarcinoma -all in the distal esophagus.A mean of 1.7±0.83endoscopic sessions were performed with a mean of six (range one to 26) sections removed in total.Three patients developed strictures following EMR; two of whom had pre-existing strictures, and the third required two dilations under conscious sedation, which completely relieved the symptoms.None of the patients sustained a perforation or hemorrhage following EMR.
Three patients in the study underwent subsequent esophagectomy.Two were patients with pre-existing strictures (as above).One had a focus of mucosal malignancy within the stricture; the other had an area of HGD within the stricture.The third patient had an adenocarcinoma not amenable to EMR because it was located in a hiatus hernia distal to the squamocolumnar junction.Following EMR, one patient underwent RFA to treat a long-segment Barrett's esophagus (Figure 3).
The remaining 18 patients were followed for a median of two years (range one to three years).Fourteen patients had no dysplasia and four had focal LGD, and continued in a surveillance program.At the time of the present report, no patient had died or developed cancer (Table 2).

DISCUSSION
EMR of the esophagus has been proposed to be an ideal method for the management of patients with either dysplasia-or mucosal-based cancers (14,15).EMR involves excision of esophageal mucosa to the level of the submucosa by applying a band (ie, suctioning mucosa to create a 'pseudopolyp') then excising and collecting the tissue.It serves both a diagnostic and therapeutic role while minimizing hospital stays and morbidity.
The Japan Gastroenterological Endoscopy Society has developed a classification system (16) to help define the indications and outcomes of EMR based on visual and endosonographic features.Ideally, those most suitable for EMR are individuals with a lesion of 2 cm or less in diameter, limited to the mucosa and involving less than one-third of the circumference of the esophagus.A helpful modality for planning EMR is endoscopic ultrasound because it enables the determination of tumour insertion depth and the assessment of regional as well as celiac lymph nodes.
A variety of EMR techniques for the treatment of Barrett's esophagus have been described.The most widely used technique is the endoscopic cap resection technique.The target lesion is first lifted by injection of a fluid sometimes containing dilute adrenaline into the submucosa.Subsequently, a transparent cap is attached to the endoscope.The cap has a distal ridge that enables positioning of a snare.The lesion is sucked into the cap thus creating a pseudopolyp that is immediately captured by forcefully closing the prepositioned snare.Finally, the lesion is removed using electrocoagulation.An alternative approach (the 'suck band-and-cut technique') does not require submucosal injection.A reusable variceal ligation device is used to suck the lesion into the ligation cap, allowing it to be captured with a rubber band.The endoscope is then removed, the ligation device is disassembled, and the endoscope is reintroduced to remove the created pseudopolyp with a standard polypectomy snare.A prospective randomized study (17) found no significant difference with respect to the size of the resected specimens or complications among the first two described techniques.Several new techniques are currently  Several studies from Europe and Japan (18)(19)(20)(21)(22) have demonstrated the safety and efficacy of EMR; however, the use of EMR in Canada has largely been unreported until now.Longterm data concerning recurrence rates are still somewhat lacking; however, published data regarding EMR of isolated lesions have been favourable thus far (23)(24)(25)(26)(27)(28)(29)(30).In a German study, Ell et al (22) documented 100 consecutive patients who were considered to have low-risk Barrett's carcinoma and reported remission in 99 patients after a maximum of three resections.During a median follow-up period of 37 months, recurrent or metachronous cancers were found in 11% of patients who were all effectively treated endoscopically.In the largest study to date (31), Japanese researchers investigated 142 patients with esophageal cancer who were followed for nine years and reported a 95% survival rate using EMR.
Complications, however infrequent, are worth mentioning because they can lead to increased morbidity and health care costs and discourage the widespread use of EMR.Therapies such as esophagectomy may be associated with high morbidity and mortality rates with long-term problems such as dysphagia (1)(2)(3)(4).PDT is associated with a 30% rate of stricture formation (32) and data regarding long-term complications from RFA techniques are lacking.EMR offers less morbidity and mortality, while being associated with fewer complication rates (Figures 4 to 6).Perforation is a rare (1%) but serious complication that has been found to increase with piecemeal resection (32).Stricture formation is also of concern; however, strictures tend to occur in patients in whom the EMR involves more than three-fourths of the circumference of the esophagus or when the resection length is greater than 3 cm (33).Nevertheless, most strictures are amenable to endoscopic dilation (33).
Our patients were treated with monotherapy EMR.We believed it was important to assess our results, particularly because newer methods of therapy (such as RFA) have become available.Although we have several patients with focal LGD remaining, there have been no major complications.Some of our patients with longer segments of remaining Barrett's esophagus or LGD may be considered for RFA or ongoing surveillance.Although the early data for RFA appear to be very promising, the cost of this treatment exceeds that of EMR, particularly for short-segment lesions.Presently, we have adjusted our management protocol using RFA (usually in combination with EMR) for long segments or those segments that are resistant to EMR.For short-segment HGD/mucosal cancers, we still advocate monotherapy with EMR, typically removing all Barrett's esophagus over two or three endoscopic sessions.

CONCLUSIONS
Most patients with localized lesions of the esophagus, particularly in shorter segments of Barrett's esophagus, can be managed with endoscopic mucosal resection.EMR is preferable to modalities such as esophagectomy and PDT, offering lower morbidity and mortality rates while achieving acquisition of the entire specimen.Longer segment Barrett's esophagus remains an issue, and other ablative therapies such as RFA appear promising.The need for specialized centres capable of performing EMR and regular endoscopic follow-up, along with the complications of EMR such as bleeding, stricture and perforation, have hindered the widespread use of EMR in Canada.Further studies need to be conducted to define the cost-benefit ratio of EMR as opposed to other modalities, as well as to study the long-term  outcomes, complication rates and utility of combination therapeutic approaches.Nevertheless, the data supporting the utility of EMR as a diagnostic and therapeutic option are apparent, and should be used in the appropriate setting.